Project Summary/Abstract: Resistance to insulin-mediated glucose disposal is now recognized as the earliest abnormality in glucose tolerant individuals (nondiabetics) who will eventually develop type 2 diabetes. In addition to being a risk factor for atherosclerosis, recent studies have established that patients with type 2 diabetes also demonstrate increased rate of restenosis after angioplasty. Our preliminary studies indicate that insulin resistance, in the absence of frank hyperglycemia, is associated with enhanced restenosis in a rat model of balloon injury, as well as increased inflammation as determined by vascular production of reactive oxygen species and enhanced expression of inflammatory genes. Moreover, insulin resistance is associated with increased circulating levels of the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine (ADMA), providing another mechanism for the accelerated restenotic response. THR-0921 is a novel insulin sensitizing compound that has potent glucose-lowering activity, modest PPAR-y activity, as well as anti-inflammatory actions. This proposal will test the efficacy of THR-0921 to inhibit restenosis in a rat model of insulin resistance as well as its effects on ADMA levels. Accordingly, we will use our in vivo model to address these specific aims: 1) To expand upon our initial findings to determine the potential therapeutic applicability of THR-0921 in the control of restenosis, particularly in the setting of insulin resistance. 2) To determine the efficacy of THR-0921 to reduce ADMA levels in insulin resistant animals. If the SBIR phase I results show activity in our animal model of insulin resistance, the goal in an SBIR phase II study will be to pursue clinical development of THR-0921 for the treatment of insulin resistance and type 2 diabetes. The goal will be to develop a potent insulin sensitizer with demonstrated effects on cardiovascular biology that has a reduced side effect profile compared with traditional thiazolidinediones. Project Narrative: People who develop diabetes as adults (type 2 diabetes) often have related conditions such as obesity that increase their risk for developing coronary heart disease. Unfortunately, the newest drugs commonly used to treat type 2 diabetes have undesired side effects that further increase the risk of heart disease. The current study is designed to evaluate a new drug in this class that not only appears to have fewer heart-related side effects, but also may help reduce complications that arise from certain surgical procedures used to treat coronary heart disease. [unreadable] [unreadable] [unreadable]